The objective of this research is to delineate the role of the Na ion plus K ion-ATPase as a pharmacological receptor in the cardiovascular system. Because this enzyme may be the receptor for the inotropic actions of the cardiac glycosides a detailed investigation of the interaction of ouabain with the Na ion plus K ion-ATPase is proposed. This will involve examination of the mechanism of ouabain binding to this enzyme, the relationship between the two patterns of ouabain binding and the factors which affect the stability of the enzyme-ouabain complex. To specifically label and analyze the (H3) ouabain binding site a photoaffinity label for the ouabain binding site is being developed. Experiments using showdomycin to specifically label the nucleotide binding site of Na ion plus K ion-ATPase are also proposed. The Na ion plus K ion-ATPase may also be the pharmacological receptor for ethacrynic acid. Experiments are outlined to determine the physiologically significant mechanism of inhibition of this enzyme by ethacrynic acid and to resolve conflicts in the literature concerning its in vivo inhibition of the Na ion plus K ion-ATPase. Studies on the interaction of the erythrophleum alkaloid cassaine with the Na ion plus K ion-ATPase are also proposed. Bibliographic references: Tobin, T., Akera, T. and Brody, T.M.: Gel electrophoretic identity of the Na ion, Mg ions and Na ion, Ca ions stimulated phosphorylations of Na ion plus K ion-ATPase. Biochem. Biophys. Acta 389: 117-125, 1975; Tobin, T. and Akera, T.: Showdomycin, a nucleotide site directed inhibitor of Na ion plus K ion-ATPase. Biochem. Biophys. Acta 389: 126-136, 1975.